This project is concerned with the study of the role of serotonin (5-HT) in the affective illnesses (depression and mania), focusing particularly on the blood platelet as a model system for studying 5-HT uptake. A reliable method has been established for the determination for the kinetic constants (Km and Vmax, measures of the affinity of the uptake system for 5-HT and the number of uptake sites, respectively) for 5-HT uptake. Km and Vmax were determined in twenty normal controls and 72 psychiatric patients of various diagnoses. A significant decrease in the Vmax for 5-HT uptake was found in unipolar and bipolar depressed patients, as well as schizo-affective depressed patients, primarily depresssed. The decrease in Vmax was particularly striking in bipolar depressed patients. No significant difference in Vmax was found among the normal controls, bipolar manic, schizoaffective manic, and schizophrenic patients. There was no difference in Km among any of the diagnostic groups. Tricyclic antidepressant treatment increased Km and, in the case of imipramine, decreased Vmax. Lithium carbonate treatment further decreased Vmax. A similar effect was found in platelets of rats treated chronically with lithium chloride. No relationship was found between treatment response to tricyclic antidepressants or lithium and baseline Vmax or change in Km. 5-HT levels in depressed patients were not significantly different from those found in normal controls.